Colorectal cancer causes 655,000 deaths worldwide per year, making it the second-leading cause of cancer-related deaths. It is the third most frequently diagnosed cancer in men and women in the United States and carries an overall population lifetime risk of 6%. (American Cancer Society. Cancer Facts and Figures. 2008. Atlanta: American Cancer Society.). The American Cancer Society estimates that about 108,070 new cases of colon cancer (53,760 in men and 54,310 in women) and 40,740 new cases of rectal cancer (23,490 in men and 17,250 in women) will be diagnosed in 2008. Of those diagnosed, nearly half are expected to die within five years. In the United States in 2008 an estimated 50,000 men and women will die of cancer of the colon and rectum. (American Cancer Society 2008). This high mortality rate is due at least in part to the fact that a large proportion of cancers are detected at relatively late stages, such as following onset of overt symptoms, when the cancer is more difficult to treat. In addition, identification of colorectal cancer at later stages concomitantly necessitates harsher treatment, such as radical colostomy. It has been shown that the identification and treatment of colorectal cancer at earlier stages significantly reduces the risk of developing more advanced disease, and hence risk of death from the disease. Stage at detection is critically related to patient survival. Localized cancers (Dukes's Stage A or B) have an excellent prognosis of 82%-93% at five years. Regional (Dukes's Stage C) patients have a five year survival rates of 55% to 60%; and only 5% to 8% of patients with late stage cancer will survive the five year span. (O'Connell J B, Maggard M, Ko C Y. Colon cancer survival rates with the new American Joint Committee on cancer sixth edition staging. JNCI. 2004; 96: 1420-1425.). Therefore, a test to screen for colorectal cancer so as to allow earlier treatment should markedly reduce the incidence of advanced-stage colorectal cancer (Ransohoff D F. Colorectal cancer screening in 2005: status and challenges. Gastroenterology. 2005 May; 128(6):1685-95) and decrease the current costs to the medical system. Thus, the American Cancer Society recommends that all Americans age 50 and older be screened regularly for colorectal cancer. Unfortunately, only a small fraction of the population at risk is screened for the disease (Mitka M. Colorectal cancer screening rates still fall far short of recommended levels. JAMA. 2008 Feb. 13; 299(6):622), as currently available screening methods require insufficiently available and/or costly resources, are associated with unacceptably low patient compliance, and/or are associated with significant health risks.
Currently utilized screening technologies to test for colorectal cancer include fecal occult blood test (FOBT), flexible sigmoidoscopy, double contrast barium enema (DCBE), and colonoscopy. The current recommended standards for screening for colorectal cancer in individuals over the age of 50 and who are considered part of an average risk population include: an FOBT yearly, a sigmoidoscopy every five years, a colonoscopy every ten years and a DCBE every five years. For a high risk population where one or more family members have had colorectal cancer, a colonoscopy is recommended every two years as a follow up to FOBT or sigmoidoscopy. Each of these tests suffers significant disadvantages. Fecal occult blood testing suffers from low sensitivity, requires significant dietary and other restrictions prior to testing and is associated with poor patient compliance. Sigmoidoscopy and colonoscopy are more sensitive than the other standard methods since they involve direct visualization of the lumen of the colon, however these methods are also associated with various significant disadvantages. Sigmoidoscopy and colonoscopy are both highly invasive procedures which cause significant levels of discomfort, causing many individuals to opt not to undergo these recommended screening procedures. Sigmoidoscopy only allows visualization of the distal part of the colon and hence cannot detect a relatively large fraction of cancers, and colonoscopy, despite allowing examination essentially along the entire length of the colon, is associated with a significant failure rate for detection of colorectal cancer. In addition, sigmoidoscopy and colonoscopy are costly, are insufficiently available, and may result in potentially lethal complications, such as accidental intestinal perforation.
Various approaches have been proposed in the prior art for colorectal cancer testing using identification and analysis of markers of this disease in blood (reviewed in Hundt S. et al. Blood markers for early detection of colorectal cancer: a systematic review. Cancer Epidemiol Biomarkers Prev. 2007 October; 16(10):1935-53). Such approaches, if successful, would have the advantage of circumventing critical disadvantages of the standard prior art methods, by virtue, for example, of being relatively non-invasive, minimally cumbersome, essentially risk-free and hence likely to be associated with increased patient screening compliance rates. However, none of these approaches has demonstrated an optimal capacity for diagnosing colorectal cancer.
Thus, there is a longstanding and urgent need for an improved method of determining a probability of colorectal cancer in a subject based on analysis of blood markers.